Modification of antitumor disulfide cytotoxicity by glutathione depletion in murine cells.

Abstract:

:Decyl and phenyl disulfide derivatives of 6-mercaptopurine and 6-thioguanine (6-TG) were examined for antineoplastic activity under aerobic and hypoxic conditions toward EMT6 cells in culture. Although these derivatives did not display selective toxicity toward the hypoxic cells, they were significantly more toxic than 6-TC to this cell line at 500 microM after a 2-h exposure. In conjunction with this cytotoxicity, these agents were found to deplete the cellular glutathione (GSH) levels to varying degrees at this same concentration after a 1-h period. Therefore, the effect of modulating the cellular GSH on the cytotoxicity of these agents was investigated. When the GSH was depleted to less than 5 or 41% of control levels, the cytotoxicity exhibited by these agents was significantly increased while that of 6-TG remained unchanged. The cytotoxicity of these agents was similar to that of decanethiol and thiophenol, the thiol portion of the molecules, both under normal treatment conditions or after depletion of GSH. The lack of selective toxicity toward hypoxic cells was correlated to the finding that the disulfides were broken down to the parents, 6-mercaptopurine, and 6-TG, by cells under aerobic conditions. However, these studies demonstrate that manipulation of GSH levels might yield a therapeutic gain for these disulfide derivatives of antitumor agents.

journal_name

Cancer Res

journal_title

Cancer research

authors

Kirkpatrick DL

subject

Has Abstract

pub_date

1987-08-15 00:00:00

pages

4391-5

issue

16

eissn

0008-5472

issn

1538-7445

journal_volume

47

pub_type

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